Renin inhibitors containing peptide isosteres

Claim 2

A peptide of the formula: wherein: A is hydrogen; or where X is -O-; -O-CH-; -CH-O-; -CH-; -NH-CH-; or -S-CH-; and R 2 a and R 2 b may be the same or different and are hydrogen; W-(CH 2 ) n - or W-(CH 2 ) m -CH=CH-(CH 2 ) p . where W is hydrogen: C 1-4 alkyl; aryl: C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; n is 0 to 5: m is 0 to 2; and p is 0 to 2: except that where X is -O-, only one of R 2 a or R 2 b is present; B is absent; glycyl; sarcosyl; or where R 1 is as defined further below; D is absent: or where Z is -(CH 2 ) 1 - and 1 is 1 or 2: or -S-: E is absent; or where m is 1 to 4: and R 5 is hydrogen; C 1-4 alkyl; aryl: aryl-C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C l-4 alkyl. trifluoromethyl. hydroxy. C 1-4 alkoxy. and halo; or indolyl; G is where q is 1 to 4: R 4 is as defined further below; R 6 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; and Q is wherein X' is hydroxy; amino; or mono-or di-C 1-4 alkyl amino; and W' is absent: -O-; -NH-: or -CH 2 -; where X" and X"' are independently absent; or and W" is absent; -CH 2 -; or where R° is hydrogen or C 1-3 alkyl; or ; where R is hydrogen: C 1-4 alkyl; formyl; C 1-4 alkanoyl; aroyl; carboxy; C 1-4 alkoxycatbonyl; aryloxycarbonyl; or aryl C 1-4 alkoxycatbonyl; J is (1) -Y-(CH 2 ) n -R 7 where Y is -NH- or -0-; n is 0 to 5: and R 7 is hydrogen; hydroxy: C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino. mono- or d i- C 1-4 alkylamino, and halo; amino; mono-, di-. or tri-C 1-4 alkylamino; guanidyl: heterocyclic: or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl. C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; (2) where Y is as defined above: n is 0 or 1: n' is 0 or 1: n" is 1 to 4: n'" is 1 to 4; and R 7 and R 7 may be the same or different and have the same meaning as R 7 above and R 7 may additionally a be where R 8 is hydrogen or C 1-3 alkyl; (3) where Y is as defined above; n is 0 or 1: and Z' is where n is 0 or 1; and R 8 is as defined above; or where n is 0 or 1: (4) where R 5 is as defined above; and R9 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; or (5) or where Y is -NH- or -O-; q is 1-5: q' is 0-5; R 10 is hydrogen: hydroxy: N(R') 2 , where R' may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl; or N ⊕ (R') 3 A ⊖ . where R' is as defined above, and A 6 is a counterion: provided that at least one R 10 is not hydrogen: R 11 is C 1-4 alkyl; C 3-7 cycloalkyl; aryl: aryl substituted with up to three members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl. hydroxy. C 1-4 alkoxy, amino, mono- or di- C 1-4 alkylamino, amino C 1-4 alkyl, mono-, di-. or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide. carboxy-C 1-4 alkoxy, carboxy-C 1-4 - alkoxy ester or amide. α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide. carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; carboxy, ester or amide; sulfo; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl. C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or R 12 is hydrogen; or carboxy, ester or amide; R 13 is c arboxy, ester or amide; sulfo; or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 -alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, a-amino- carboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; and R 14 is carboxy, ester or amide; or or where Y is -NH- or -O-: k is 0-4; k' is 0 or 1; k" is 0-4: k"'is 0 or 1; R' is hydrogen or C 1-4 alkyl; and R" is hydrogen or C 1-4 alkyl; L is absent: OR": NHR": or N(R") 2 , where R" may be the same or different and is hydrogen or C 1-4 alkyl; provided that. B adjacent J and/or L are present only when J is defined as in J (4) above; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl: aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl. trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo: indolyl; 4-imidazolyl: amino C 2-4 alkyl; acyl C 2-4 alkyl wherein the acyl is and R 9 is as defined above: guanidyl C 2-3 alkyl; or methylthiomethyl: R 4 is hydrogen: or where R is as defined above; and R 3 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo: or indolyl; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D. and Q portion of G substituents, which may have an S or R configuration: and a pharmaceutically acceptable salt thereof.

Claim 3

A peptide according to Claim 1 wherein the peptide is a member selected from the group consisting essentially of:

Claim 4

A pharmaceutical composition for treating renin-associated hypertension, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: wherein: A is hydrogen: or where X is or -S-CH-; and R 2 a and R 2 b may be the same or different and are hydrogen; W-(CH 2 ) n - or W-(CH 2 ) m -CH=CH-(CH 2 ) p , where W is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl, or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo: n is 0 to 5: m is 0 to 2; and p is 0 to 2; except that where X is -0-, only one of R 2 a or R 2 b is present; B is absent; glycyl; sarcosyl: or where R 1 is as defined further below: D is absent; or . where Z is -(CH 2 ) 1 - and 1 is 1 or 2: or -S-: E is absent: or , where m is 1 to 4: and R 5 is hydrogen; C l-4 alkyl: aryl; aryl-C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy, C 1-4 alkoxy, and halo: or indolyl: G is where q is 1 to 4; R 4 is as defined further below: R 6 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl: or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl. trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo; and Q is wherein X' is hydroxy; amino; or mono-or di-C 1-4 alkyl amino: and W' is absent; -O-; -NH-: or -CH 2 -: where X" and X"' are independently absent; or and W" is absent; -CH 2 -; or where R° is hydrogen or C 1-3 alkyl: or ; where R is hydrogen: C 1-4 alkvl: formvl: C 1-4 alkanoyl: aroyl; carboxy; C 1-4 alkoxycarbonyl: aryloxycarbonyl: or aryl C 1-4 alkoxycarbonyl; (1) -Y-(CH 2 ) n -R 7 where Y is -NH- or -O-; n is 0 to 5: and R 7 is hydrogen; hydroxy; C 1-4 alkyl: C 3-7 cycloalkyl: aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or d i- C 1-4 alkylamino, and halo; amino: mono-. di-. or tri-C 1-4 alkylamino: guanidyl: heterocyclic: or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy. trifluocomethyl, C 1-4 alkoxy, halo. aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; (2) where Y is as defined above; n is 0 or 1: n' is 0 or 1: n" is 1 to 4; n'" is 1 to 4; and R 7 and R 7 a may be the same or different and have the same meaning as R 7 above and R 7 a may additionally be where R 8 is hydrogen or C 1-3 alkyl; (3) where Y is as defined above; n is 0 or 1: and Z' is where n is 0 or 1: and R 8 is as defined above: or where n is 0 or 1; (4) . where R 5 is as defined above; and R 9 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; or (5) or where Y is -NH- or -O-; q is 1-5; q' is 0-5: R 10 is hydrogen: hydroxy; N(R') 2 . where R' may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl: or N⊕(R') 3 A⊖, where R' is as defined above, and A 8 is a counterion; provided that at least one R 10 is not hydrogen; R 11 is C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to three members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl. hydroxy, C 1-4 alkoxy, amino. mono- or di- C 1-4 alkylamino, amino C 1-4 alkyl, mono-, di-, or tri-C 1-4 alkylamino-C 1-4 alkyl, halo. carboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 - alkoxy ester or amide, a-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide. guanidyl, and guanidyl-C 1-4 alkyl; carboxy. ester or amide; sulfo; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy. trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; R 12 is hydrogen; or carboxy. ester or amide; R 13 is carboxy, ester or amide; sulfo: or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 -alkylamino-C 1-4 - alkyl, halo, carboxy, carboxy ester or amide. carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, a-amino- carboxy-C 1-4 alkyl, a-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; and R 14 is carboxy, ester or amide: or or where Y is -NH- or -O-; k is 0-4; k' is 0 or 1; k" is 0-4: k"'is 0 or 1; R' is hydrogen or C 1-4 alkyl; and R" is hydrogen or C 1-4 alkyl; L is absent: OR": NHR": or N(R") 2 , where R" may be the same or different and is hydrogen or C 1-4 alkyl; provided that, B adjacent J and/or L are present only when J is defined as in J (4) above; R 1 is hydrogen; C 1-4 alkyl: hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl. trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo: indolyl; 4-imidazolyl; amino C 2-4 alkyl; acyl C 2-4 alkyl wherein the acyl is and R 9 is as defined above: guanidyl C 2-3 alkyl: or methylthiomethyl: R 4 is hydrogen; or , where R 9 is as defined above; and R 3 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo; or indolyl: and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B. D, and Q portion of G substituents, which may have an S or R configuration: and a pharmaceutically acceptable salt thereof.

Claim 5

A pharmaceutical composition for treating renin-associated hypertension, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: wherein: A is hydrogen: or where X is or -S-CH-; and R 2 a and R 2 b may be the same or different and are hydrogen; W-(CH 2 ) n - or W-(CH 2 ) m -CH=CH-(CH 2 ) p , where W is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl, or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo: n is 0 to 5: m is 0 to 2; and p is 0 to 2; except that where X is -0-, only one of R 2 a or R 2 b is present; B is absent; glycyl; sarcosyl: or where R 1 is as defined further below: D is absent; or . where Z is -(CH 2 ) 1 - and 1 is 1 or 2: or -S-: E is absent: or , where m is 1 to 4: and R 5 is hydrogen; C l-4 alkyl: aryl; aryl-C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy, C 1-4 alkoxy, and halo: or indolyl: G is where q is 1 to 4; R 4 is as defined further below: R 6 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl: or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl. trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo; and Q is wherein X' is hydroxy; amino; or mono-or di-C 1-4 alkyl amino: and W' is absent; -O-; -NH-: or -CH 2 -: where X" and X"' are independently absent; or and W" is absent; -CH 2 -; or where R° is hydrogen or C 1-3 alkyl: or ; where R is hydrogen: C 1-4 alkvl: formvl: C 1-4 alkanoyl: aroyl; carboxy; C 1-4 alkoxycarbonyl: aryloxycarbonyl: or aryl C 1-4 alkoxycarbonyl; (1) -Y-(CH 2 ) n -R 7 where Y is -NH- or -O-; n is 0 to 5: and R 7 is hydrogen; hydroxy; C 1-4 alkyl: C 3-7 cycloalkyl: aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or d i- C 1-4 alkylamino, and halo; amino: mono-. di-. or tri-C 1-4 alkylamino: guanidyl: heterocyclic: or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy. trifluocomethyl, C 1-4 alkoxy, halo. aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; (2) where Y is as defined above; n is 0 or 1: n' is 0 or 1: n" is 1 to 4; n'" is 1 to 4; and R 7 and R 7 a may be the same or different and have the same meaning as R 7 above and R 7 a may additionally be where R 8 is hydrogen or C 1-3 alkyl; (3) where Y is as defined above; n is 0 or 1: and Z' is where n is 0 or 1: and R 8 is as defined above: or where n is 0 or 1; (4) . where R 5 is as defined above; and R 9 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; or (5) or where Y is -NH- or -O-; q is 1-5; q' is 0-5: R 10 is hydrogen: hydroxy; N(R') 2 . where R' may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl: or N⊕(R') 3 A⊖, where R' is as defined above, and A 8 is a counterion; provided that at least one R 10 is not hydrogen; R 11 is C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to three members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl. hydroxy, C 1-4 alkoxy, amino. mono- or di- C 1-4 alkylamino, amino C 1-4 alkyl, mono-, di-, or tri-C 1-4 alkylamino-C 1-4 alkyl, halo. carboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 - alkoxy ester or amide, a-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide. guanidyl, and guanidyl-C 1-4 alkyl; carboxy. ester or amide; sulfo; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy. trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; R 12 is hydrogen; or carboxy. ester or amide; R 13 is carboxy, ester or amide; sulfo: or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 -alkylamino-C 1-4 - alkyl, halo, carboxy, carboxy ester or amide. carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, a-amino- carboxy-C 1-4 alkyl, a-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; and R 14 is carboxy, ester or amide: or or where Y is -NH- or -O-; k is 0-4; k' is 0 or 1; k" is 0-4: k"'is 0 or 1; R' is hydrogen or C 1-4 alkyl; and R" is hydrogen or C 1-4 alkyl; L is absent: OR": NHR": or N(R") 2 , where R" may be the same or different and is hydrogen or C 1-4 alkyl; provided that, B adjacent J and/or L are present only when J is defined as in J (4) above; R 1 is hydrogen; C 1-4 alkyl: hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl. trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo: indolyl; 4-imidazolyl; amino C 2-4 alkyl; acyl C 2-4 alkyl wherein the acyl is and R 9 is as defined above: guanidyl C 2-3 alkyl: or methylthiomethyl: R 4 is hydrogen; or , where R 9 is as defined above; and R 3 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo; or indolyl: and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B. D, and Q portion of G substituents, which may have an S or R configuration: and a pharmaceutically acceptable salt thereof.

Claim 6

A composition according to Claim 3 wherein the peptide is a member selected from the group consisting essentially of:

Claim 7

A pharmaceutical composition for treating renin-associated hyperaldosteronism. comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: wherein: A is hydrogen; or where X is -O-; ; or ; and R 2 a and R 2 b may be the same or different and are hydrogen: W-(CH 2 ) n - or W-(CH 2 ) m -CH=CH-(CH 2 ) p . where W is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo; n is 0 to 5: m is 0 to 2: and p is 0 to 2; except that where X is -O-, only one of R 2 a or R 2 b is present; B is absent; glycyl: sarcosyl; or where R 1 is as defined further below; D is absent; or . where Z is -(CH 2 ) 1 - and 1 is 1 or 2: or -S-: E is absent; or where m is 1 to 4; and R 5 is hydrogen; C 1-4 alkyl; aryl: aryl-C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl. trifluoromethyl. hydroxy. C 1-4 alkoxy, and halo: or indolyl: G is where q is 1 to 4; R 4 is as defined further below; R 6 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy. C 1-4 alkoxy, and halo; and Q is wherein X' is hydroxy; amino: or mono-or di-C 1-4 alkyl amino; and W' is absent; -O-; -NH-; or -CH 2 -; where X" and X"' are independently absent; or and W" is absent; -CH 2 -; or where R is hydrogen or C 1-3 alkyl; or : where R is hydrogen: C 1-4 alkyl; formyl; C 1-4 alkanoyl; aroyl; carboxy; C 1-4 alkoxycarbonyl: aryloxycarbonyl; or aryl C 1-4 alkoxycarbonyl; is (1) -Y-(CA 2 ) n -R 7 where Y is -NH- or -O-; n is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, amino, mono- or di- C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl. C 1-4 alkoxy, halo. aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; where Y is as defined above: n is 0 or 1; n' is 0 or 1; n" is 1 to 4: n'" is 1 to 4; and Rand R 7 may be the same or different and have the same meaning as R 7 above and R 7 may additionally be where R 8 is hydrogen or C 1-3 alkyl: where Y is as defined above: n is 0 or 1: and Z' is where n is 0 or 1; and R 8 is as defined above; or where n is 0 or 1: (4) . where R 5 is as defined above; and R 9 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl: or (5) or where Y is -NH- or -O-; q is 1-5: q' is 0-5: R 10 is hydrogen; hydroxy: N(R') 2 , where R' may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl; or N⊕(R') 3 A⊖, where R' is as defined above, and A⊖ is a counterion: provided that at least one R 10 is not hydrogen; R 11 is C 1-4 alkyl: C 3-7 cycloalkyl; aryl: aryl substituted with up to three members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or di- C 1-4 alkylamino, amino C 1-4 alkyl, mono-, di-, or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy. carboxy ester or amide. carboxy-C 1-4 alkoxy, carboxy-C 1-4 - alkoxy ester or amide. α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl: carboxy, ester or amide: sulfo: heterocyclic: or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl. C 1-4 alkoxy, halo, acyl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; R 12 is hydrogen; or carboxy, ester or amide; R is carboxy, ester or amide; sulfo; or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-. or tri-C 1-4 -alkylamino-C 1-4 - alkyl, halo. carboxy. carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, α-amino- carboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl. carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; and R 14 is carboxy, ester or amide; or or where Y is -NH- or -0-: k is 0-4; k' is 0 or 1; k" is 0-4: k"'is 0 or 1; R' is hydrogen or C 1-4 alkyl; and R" is hydrogen or C 1-4 alkyl: L is absent: OR"; NHR"; or N(R") 2 , where R" may be the same or different and is hydrogen or C 1-4 alkyl; provided that. B adjacent J and/or L are present only when J is defined as in J (4) above;. R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl: aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy. C 1-4 alkoxy, and halo; indolyl: 4-imidazolyl; amino C 2-4 alkyl; acyl C 2-4 alkyl wherein the acyl is R 9 and R 9 is as defined above; guanidyl C 2-3 alkyl; or methylthiomethyl; R 4 is hydrogen; or . where R 9 is as defined above; and R 3 is hydrogen: C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo: or indolyl: and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B. D, and Q portion of G substituents, which may have an S or R configuration: and a pharmaceutically acceptable salt thereof.

Claim 8

A pharmaceutical composition for treating renin-associated hyperaldosteronism. comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: wherein: A is hydrogen; or where X is -O-; ; or ; and R 2 a and R 2 b may be the same or different and are hydrogen: W-(CH 2 ) n - or W-(CH 2 ) m -CH=CH-(CH 2 ) p . where W is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo; n is 0 to 5: m is 0 to 2: and p is 0 to 2; except that where X is -O-, only one of R 2 a or R 2 b is present; B is absent; glycyl: sarcosyl; or where R 1 is as defined further below; D is absent; or . where Z is -(CH 2 ) 1 - and 1 is 1 or 2: or -S-: E is absent; or where m is 1 to 4; and R 5 is hydrogen; C 1-4 alkyl; aryl: aryl-C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl. trifluoromethyl. hydroxy. C 1-4 alkoxy, and halo: or indolyl: G is where q is 1 to 4; R 4 is as defined further below; R 6 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy. C 1-4 alkoxy, and halo; and Q is wherein X' is hydroxy; amino: or mono-or di-C 1-4 alkyl amino; and W' is absent; -O-; -NH-; or -CH 2 -; where X" and X"' are independently absent; or and W" is absent; -CH 2 -; or where R is hydrogen or C 1-3 alkyl; or : where R is hydrogen: C 1-4 alkyl; formyl; C 1-4 alkanoyl; aroyl; carboxy; C 1-4 alkoxycarbonyl: aryloxycarbonyl; or aryl C 1-4 alkoxycarbonyl; is (1) -Y-(CA 2 ) n -R 7 where Y is -NH- or -O-; n is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, amino, mono- or di- C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl. C 1-4 alkoxy, halo. aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; where Y is as defined above: n is 0 or 1; n' is 0 or 1; n" is 1 to 4: n'" is 1 to 4; and Rand R 7 may be the same or different and have the same meaning as R 7 above and R 7 may additionally be where R 8 is hydrogen or C 1-3 alkyl: where Y is as defined above: n is 0 or 1: and Z' is where n is 0 or 1; and R 8 is as defined above; or where n is 0 or 1: (4) . where R 5 is as defined above; and R 9 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl: or (5) or where Y is -NH- or -O-; q is 1-5: q' is 0-5: R 10 is hydrogen; hydroxy: N(R') 2 , where R' may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl; or N⊕(R') 3 A⊖, where R' is as defined above, and A⊖ is a counterion: provided that at least one R 10 is not hydrogen; R 11 is C 1-4 alkyl: C 3-7 cycloalkyl; aryl: aryl substituted with up to three members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or di- C 1-4 alkylamino, amino C 1-4 alkyl, mono-, di-, or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy. carboxy ester or amide. carboxy-C 1-4 alkoxy, carboxy-C 1-4 - alkoxy ester or amide. α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl: carboxy, ester or amide: sulfo: heterocyclic: or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl. C 1-4 alkoxy, halo, acyl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; R 12 is hydrogen; or carboxy, ester or amide; R is carboxy, ester or amide; sulfo; or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-. or tri-C 1-4 -alkylamino-C 1-4 - alkyl, halo. carboxy. carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, α-amino- carboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl. carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; and R 14 is carboxy, ester or amide; or or where Y is -NH- or -0-: k is 0-4; k' is 0 or 1; k" is 0-4: k"'is 0 or 1; R' is hydrogen or C 1-4 alkyl; and R" is hydrogen or C 1-4 alkyl: L is absent: OR"; NHR"; or N(R") 2 , where R" may be the same or different and is hydrogen or C 1-4 alkyl; provided that. B adjacent J and/or L are present only when J is defined as in J (4) above;. R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl: aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy. C 1-4 alkoxy, and halo; indolyl: 4-imidazolyl; amino C 2-4 alkyl; acyl C 2-4 alkyl wherein the acyl is R 9 and R 9 is as defined above; guanidyl C 2-3 alkyl; or methylthiomethyl; R 4 is hydrogen; or . where R 9 is as defined above; and R 3 is hydrogen: C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo: or indolyl: and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B. D, and Q portion of G substituents, which may have an S or R configuration: and a pharmaceutically acceptable salt thereof.

Claim 9

A combination for treating hypertension comprising a peptide of the formula: wherein: A is hydrogen; or where X is -O-; ; or ; and Rand R 2 b may be the same or different and are hydrogen: W-(CH 2 ) n - or W-(CH 2 ) m -CH=CH-(CH 2 ) p . where W is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl. hydroxy, C 1-4 alkaxy, and halo; n is 0 to 5: m is 0 to 2; and p is 0 to 2; except that where X is -O-, only one of R 2 or R 2 b is present; B is absent; glycyl; sarcosyl; or where R is as defined further below: D is absent: or . where Z is -(CH 2 ) 1 - and 1 is 1 or 2: or -S-: E is absent: or where m is 1 to 4; and R 5 is hydrogen: C 1-4 alkyl: aryl; aryl-C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluocomethyl, hydcoxy, C 1-4 alkoxy, and halo: or indolyl; G is where q is 1 to 4: R 4 is as defined further below; R 6 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo; and Q is wherein X' is hydroxy; amino; or mono-or di-C 1-4 alkyl amino: and W' is absent; -O-; -NH-: or -CH 2 -; where X" and X"' are independently absent; or and W" is absent; where R 8 is hydrogen or C 1-3 alkyl: or ; where R is hydrogen; C 1-4 alkyl: formyl; C 1-4 alkanoyl; aroyl: carboxy; C 1-4 alkoxycarbonyl; aryloxycarbonyl: or aryl C 1-4 alkoxycarbonyl: J is (1) -Y-(CH 2 ) n -R 7 where Y is -NH- or -O-; n is 0 to 5: and R 7 is hydrogen: hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl: aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, amino. mono- or d i- C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1-4 alkylamino: guanidyl; heterocyclic: or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy. trifluoromethyl. C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; (2) - where Y is as defined above: n is.0 or 1; n' is 0 or 1; n" is 1 to 4; n'" is 1 to 4; and R 7 and R 7 a may be the same or a different and have the same meaning as R 7 above and R 7 may additionally a be where R 8 is hydrogen or C 1-3 alkyl; (3) where Y is as defined above; n is 0 or 1; and Z' is where n is O or 1; and R 8 is as defined above: or where n is 0 or 1: (4) , where R 5 is as defined above: and R 9 is hydrogen: C 1-4 alkyl: hydroxy: or Ccyclolkyl: or (5) or where Y is -NH- or -O-; q is 1-5: q' is 0-5; R 10 is hydrogen: hydroxy: N(R') 2 , where R' may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl; or N + (R') 3 A , where R' is as defined above, and A― is a counterion; provided that at least one 8 10 is not hydrogen: R 11 is C 1-4 alkyl; C 3-7 cycloalkyl; aryl: aryl substituted with up to three members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, amino. mono- or di- C 1-4 alkylamino. amino C 1-4 alkyl, mono-, di-. or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide. cacboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, a-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; carboxy, ester or amide; sulfo; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl. C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; R 12 is hydrogen; or carboxy, ester or amide; R 13 is carboxy, ester or amide; sulfo: or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 -alkylamino-C 1-4 - alkyl. halo, catboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide. α-amino- carboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl: and R 14 is carboxy, ester or amide; or or where Y is -NH- or -O-; k is 0-4; k' is 0 or 1; k" is 0-4; k''' is 0 or 1; R' is hydrogen or C 1-4 alkyl: and R" is hydrogen or C 1-4 alkyl: L is absent; OR": NHR": or N(R") 2 , where R" may be the same or different and is hydrogen or C 1-4 alkyl; provided that, B adjacentJ and/or L are present only when J is defined as in J (4) above; R 1 is hydrogen; C 1-4 alkyl: hydroxy C 1-4 alkyl: aryl: aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy. C 1-4 alkoxy, and halo; indolyl: 4-imidazolyl: amino C 2-4 alkyl; acyl C 2-4 alkyl wherein the acyl is and R is as defined above; guanidyl C 2-3 alkyl; or methylthiomethyl: R 4 is hydrogen; or where R is as defined above: and R 3 is hydrogen: C 1-4 alkyl: aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy, C 1-4 alkoxy, and halo; or indolyl; and wherein all of the asymmetric carbon atoms have aa S configuration, except for those in the B. D, and Q portion of G substituents, which may have an S or R configuration: and a pharmaceutically acceptable salt thereof; and one or more antihypertensive agents selected from the group consisting essentially of:

Claim 10

A combination for treating hypertension comprising a peptide of the formula: wherein: A is hydrogen; or where X is -O-; ; or ; and Rand R 2 b may be the same or different and are hydrogen: W-(CH 2 ) n - or W-(CH 2 ) m -CH=CH-(CH 2 ) p . where W is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl. hydroxy, C 1-4 alkaxy, and halo; n is 0 to 5: m is 0 to 2; and p is 0 to 2; except that where X is -O-, only one of R 2 or R 2 b is present; B is absent; glycyl; sarcosyl; or where R is as defined further below: D is absent: or . where Z is -(CH 2 ) 1 - and 1 is 1 or 2: or -S-: E is absent: or where m is 1 to 4; and R 5 is hydrogen: C 1-4 alkyl: aryl; aryl-C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluocomethyl, hydcoxy, C 1-4 alkoxy, and halo: or indolyl; G is where q is 1 to 4: R 4 is as defined further below; R 6 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, and halo; and Q is wherein X' is hydroxy; amino; or mono-or di-C 1-4 alkyl amino: and W' is absent; -O-; -NH-: or -CH 2 -; where X" and X"' are independently absent; or and W" is absent; where R 8 is hydrogen or C 1-3 alkyl: or ; where R is hydrogen; C 1-4 alkyl: formyl; C 1-4 alkanoyl; aroyl: carboxy; C 1-4 alkoxycarbonyl; aryloxycarbonyl: or aryl C 1-4 alkoxycarbonyl: J is (1) -Y-(CH 2 ) n -R 7 where Y is -NH- or -O-; n is 0 to 5: and R 7 is hydrogen: hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl: aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, amino. mono- or d i- C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1-4 alkylamino: guanidyl; heterocyclic: or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy. trifluoromethyl. C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; (2) - where Y is as defined above: n is.0 or 1; n' is 0 or 1; n" is 1 to 4; n'" is 1 to 4; and R 7 and R 7 a may be the same or a different and have the same meaning as R 7 above and R 7 may additionally a be where R 8 is hydrogen or C 1-3 alkyl; (3) where Y is as defined above; n is 0 or 1; and Z' is where n is O or 1; and R 8 is as defined above: or where n is 0 or 1: (4) , where R 5 is as defined above: and R 9 is hydrogen: C 1-4 alkyl: hydroxy: or Ccyclolkyl: or (5) or where Y is -NH- or -O-; q is 1-5: q' is 0-5; R 10 is hydrogen: hydroxy: N(R') 2 , where R' may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl; or N + (R') 3 A , where R' is as defined above, and A― is a counterion; provided that at least one 8 10 is not hydrogen: R 11 is C 1-4 alkyl; C 3-7 cycloalkyl; aryl: aryl substituted with up to three members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy. C 1-4 alkoxy, amino. mono- or di- C 1-4 alkylamino. amino C 1-4 alkyl, mono-, di-. or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide. cacboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, a-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; carboxy, ester or amide; sulfo; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl. C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; R 12 is hydrogen; or carboxy, ester or amide; R 13 is carboxy, ester or amide; sulfo: or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 -alkylamino-C 1-4 - alkyl. halo, catboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide. α-amino- carboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl: and R 14 is carboxy, ester or amide; or or where Y is -NH- or -O-; k is 0-4; k' is 0 or 1; k" is 0-4; k''' is 0 or 1; R' is hydrogen or C 1-4 alkyl: and R" is hydrogen or C 1-4 alkyl: L is absent; OR": NHR": or N(R") 2 , where R" may be the same or different and is hydrogen or C 1-4 alkyl; provided that, B adjacentJ and/or L are present only when J is defined as in J (4) above; R 1 is hydrogen; C 1-4 alkyl: hydroxy C 1-4 alkyl: aryl: aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy. C 1-4 alkoxy, and halo; indolyl: 4-imidazolyl: amino C 2-4 alkyl; acyl C 2-4 alkyl wherein the acyl is and R is as defined above; guanidyl C 2-3 alkyl; or methylthiomethyl: R 4 is hydrogen; or where R is as defined above: and R 3 is hydrogen: C 1-4 alkyl: aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl. hydroxy, C 1-4 alkoxy, and halo; or indolyl; and wherein all of the asymmetric carbon atoms have aa S configuration, except for those in the B. D, and Q portion of G substituents, which may have an S or R configuration: and a pharmaceutically acceptable salt thereof; and one or more antihypertensive agents selected from the group consisting essentially of:

Claim 11

Diuretics: acetazoiamide; amiloride: bendroflumethiazide: benzthiazide: bumetanide; chlorothiazide: chlorthalidone: cyclothiazide: ethacrynic acid; furosemide; hydrochlorothiazide: hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer alone, or a manipulated ratio, e.g.. 9:1 of said enantiomers. respectively); metolazone: methyclothiazide: muzolimine: polythiazide: quinethazone: sodium ethacrynate: sodium nitroprusside: spironolactone: ticrynafen: triamterene: trichlormethiazide;

Claim 12

Diuretics: acetazoiamide; amiloride: bendroflumethiazide: benzthiazide: bumetanide; chlorothiazide: chlorthalidone: cyclothiazide: ethacrynic acid; furosemide; hydrochlorothiazide: hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer alone, or a manipulated ratio, e.g.. 9:1 of said enantiomers. respectively); metolazone: methyclothiazide: muzolimine: polythiazide: quinethazone: sodium ethacrynate: sodium nitroprusside: spironolactone: ticrynafen: triamterene: trichlormethiazide;

Claim 13

α-Adrenergic Blockina Acrents: dibenamine; phentolamine: phenoxybenzamine: prazosin: tolazoline:

Claim 14

α-Adrenergic Blockina Acrents: dibenamine; phentolamine: phenoxybenzamine: prazosin: tolazoline:

Claim 15

-Adreneraric Blockincr Agents: atenolol; metoprolol: nadolol: propranolol: timolol; ((±)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-2-furan- anilide) (ancarolol); (2-acetyl-7-( 2 -hydroxy-3-isopropylaminopropoxy)benzofuran HCl) (befunolol): ((±)-1-(isopropylamino)-3-(p-(2-cyclopropylmethoxyethyl)-phenoxy)-2-propranol HC1) (betaxolol): (1-[(3.4-dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol HC1) (bevantolol); (((±)-1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isa- propylamino-2-propanol)fumarate) (bisoprolol): (4-(2-hydroxy-3-[4-(phenoxymethyl)-piperidino]-propoxy)-indole); (carbazolyl-4-oxy-5.2-(2-methoxyphenoxy)-ethylamino-2-propanol); (1-((1.1-dimethylethyl)amino)-3-((2-methyl-1H-indol-4-yl)oxy)-2-propanol benzoate) (bopindolol); (1-(2-exabicyclo[2.2.1]-hept-2-ylphenaxy)-3-[(1-methylethyl)-amino]-2-propanol HC1) (bornaprolol); (o-[2-hydraxy-3-[(2-indol-3-yl-1.1-dimethylethyl)-amino]propoxy]benzonitrile HCI) (bucindolol): (α-[(tert.butylamino)methyl]--ethyl-2-benzafuran- methanol) (bufuralol); (3-[3-acetyl-4-[3-(tert.butylamino)-2-hydroxypropyl]-phenyl]-1.1-diethylurea HC1) (celiprolol); ((±)-2-[2-[3-[(1.1-dimethylethyl)amina]-2-hydroxy- propoxy]phenoxy]-N-methylacetamide HC1) (cetamolol): (2-benzimidazolyl-phenyl(2-isopropylaminapropanol)); ((±)-3'-acetyl-4'-(2-hydroxy-3-isoprapylaminopropoxy)-acetanilide HC1) (diacetolol); (methyl-4-[2-hydroxy-3-[(1-methylethyl)aminopropoxy]]-benzenepropanoate HC1) (esmolol): (erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol): (1-(tert.butylamino)-3-[O-(2-propynyloxy)phenoxy]-2-propanol (pargolol): (1-(tert.butylamino)-3-[o-(6-hydrazinv-3-pyridazinyl)-phenoxy]-2-propanol diHCl) (prizidilol); ((-)-2-hydroxy-5-[(R)-1-hydroxy-2-[(R)-(1-methyl-3-phenylpropyl)amino]ethyl]benzamide); (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)-propoxy]-7-methyl-5H-furo[3,2-g][1]-benzopyran-5-one) (iprocrolol): ((-)-5-(tert.butylamino)-2-hydroxypropoxy]-3,4-dihydro-1-(2H)-naphthalenone HC1) (levobunolol): (4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benziso- thiazole HC1); (4-[3-(tert.butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril HC1): ((±)-N-2-[4-(2-hydroxy-3-isopropyl aminopropoxy)-phenyl]ethyl-N'-isopropylurea) (pafenolol); (3-[[(2-trifluoroacetamido)ethyl]amino]-1-phenoxy- propan-2-ol): (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro-2.3-dihydro-3-oxo-5-pyridazinyl)ethylenediamine): ((±)-N-[3-acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]-propoxy]phenyl]butanamide) (acebutolol); ((±)-4'-[3-(tert-butylamino)-2-hydroxypropoxy]spiro-[cyclohexane-1,2'-indan]-1'-one) (spirendolol); (7-[3-[[2-hydroxy-3-[(2-methylindol-4-yl)oxy]propyl]-amino]butyl]thiophylline) (teoprolol): ((±)-1-tert.butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tertatolol); ((±)-1-tert.butylamino-3-(2,3-xylyloxy)-2-propanol HC1) (xibenolol): (8-[3-(tert.butylamino)-2-hydroxypropoxy]-5-methyl- coumarin) (bucumolol): (2-(3-·(tert.butylamino)-2-hydroxy-propoxy)benzonitrile HC1) (bunitrolol): ((±)-2'-[3-(tert-butylamino)-2-hydroxypropoxy-5'-fluorobutyrophenone) (butofilolol): (]1-(carbazol-4-yloxy)-3-(isopropylamino)-2-propanol) (carazolol); (5-(3-tert.butylamino-2-hydroxy)peopoxy-3,4-dihydro- carbostyril HC1) (carteolol): (1-(tert.butylamino)-3-(2.5-dichlorophenoxy)-2-propanol) (cloranolol); (1-(inden-4(or 7)-yloxy)-3-(isopropylamino)-2-propanol HC1) (indenolol); (1-isopropylamino-3-[(2-methylindol-4-yl)oxy]-2-propanol) (mepindolol): (1-(4-acetoxy-2.3.5-trimethylphenoxy)-3-isopropylaminopropan-2-ol) (metipranolol); (1-(isopropylamino)-3-(o-methoxyphenoxy)-3-[(1-methyi- ethyl)amino]-2-propanol) (moprolol); ((1-tert.butylamino)-3-[(5:6,7,8-tetrahydro-cis-6,7-dihydroxy-l-naphthyl)oxy]-2-propanol) (nadolol); ((S)-1-(2-cyclopentylphenoxy)-3-[(1,1-dimethylethyl)-amino]-2-propanol sulfate (2:1)) (penbutolol); (4'-[1-hydroxy-2-(amino)ethyl]methanesulfonanilide) (sotalol); (2-methyl-3-[4-(2-hydroxy-3-tert.butylaminopropoxy)-phenyl]-7-methoxy-isoquinolin-l-(2H)-one); (1-(4-(2-(4-fluorophenyloxy)ethoxy)phenoxy)-3-iso- propylamino-2-propanol HC1): ((-)-p-[3-[(3,4-dimethoxyphenethyl)amino]-2-hydroxy- propoxy]-B-methylcinnamonitrile) (pacrinolol); ((±)-2-(3'-tert.butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole HC1) (arotinolol); ((±)-1-[p-[2-(cyclopropylmethoxy)ethoxy]phenoxy]-3-(isopropylamino)-2-propanol) (cicloprolol); ((±)-1-[(3-chloro-2-methylindol-4-yl)oxy]-3-[(2-phenoxyethyl)amino]-2-propanol) (indopanolol); ((±)-6-[[2-[[3-(p-butoxyphenoxy)-2-hydroxypropylj- amino]ethyljaminoj-1,3-dimethyluracil) (pirepolol): (4-(cyclohexylamino)-1-(1-naphtholenyloxy)-2-butanol); (1-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropylj- aminaethylJhydantoin HC1); (3.4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-benzopyran) (nipradolol); a and B-Adreneraic Blockinar Agents: ((±)-1-tert-butylamino)-3-[o-[2-(3-methyl-5-isoxazolyl)vinyi]phenoxy]-2-propanol) (isoxaprolol): (1-isopropylamino-3-(4-(2-nitroxyethoxy)phenoxy)-2-propanol HC1): (4-hydroxy-cx-[[3-(4-methoxyphenyl)-1-methylpropyl]-aminomethyl]-3-(methylsulfinyl)-benzmethanol HC1) (sulfinalol): (5-[1-hydroxy-2-[[2-(o-methoxyphenoxy)ethyl]amino]-ethyl]-2-methylbenzenesulfonamide HC1); (5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-salicylamide HC1) (labetalol); (1-((3-chloro-2-methyl-1H-indol-4-yl)oxy)-3-((2-phenoxyethyl)amino)-2-propanol-hydrogenmalonate) (ifendolol): (4-(2-hydroxy-3-[(1-methyl-3-phenylpropyl)amino]-propoxy)benzeneacetamide): (1-[3-[[3-(1-naphthoxy)-2-hydroxypropyl]-amino]-3.3-dimethyl-propyl]-2-benzimidazolinone): (3-(1-(2-hydroxy-2-(4-chlorophenylethyl)-4-piperidyl)-3.4-dihydroxy)quinoxolin-2(1H)-one);

Claim 16

-Adreneraric Blockincr Agents: atenolol; metoprolol: nadolol: propranolol: timolol; ((±)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-2-furan- anilide) (ancarolol); (2-acetyl-7-( 2 -hydroxy-3-isopropylaminopropoxy)benzofuran HCl) (befunolol): ((±)-1-(isopropylamino)-3-(p-(2-cyclopropylmethoxyethyl)-phenoxy)-2-propranol HC1) (betaxolol): (1-[(3.4-dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol HC1) (bevantolol); (((±)-1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isa- propylamino-2-propanol)fumarate) (bisoprolol): (4-(2-hydroxy-3-[4-(phenoxymethyl)-piperidino]-propoxy)-indole); (carbazolyl-4-oxy-5.2-(2-methoxyphenoxy)-ethylamino-2-propanol); (1-((1.1-dimethylethyl)amino)-3-((2-methyl-1H-indol-4-yl)oxy)-2-propanol benzoate) (bopindolol); (1-(2-exabicyclo[2.2.1]-hept-2-ylphenaxy)-3-[(1-methylethyl)-amino]-2-propanol HC1) (bornaprolol); (o-[2-hydraxy-3-[(2-indol-3-yl-1.1-dimethylethyl)-amino]propoxy]benzonitrile HCI) (bucindolol): (α-[(tert.butylamino)methyl]--ethyl-2-benzafuran- methanol) (bufuralol); (3-[3-acetyl-4-[3-(tert.butylamino)-2-hydroxypropyl]-phenyl]-1.1-diethylurea HC1) (celiprolol); ((±)-2-[2-[3-[(1.1-dimethylethyl)amina]-2-hydroxy- propoxy]phenoxy]-N-methylacetamide HC1) (cetamolol): (2-benzimidazolyl-phenyl(2-isopropylaminapropanol)); ((±)-3'-acetyl-4'-(2-hydroxy-3-isoprapylaminopropoxy)-acetanilide HC1) (diacetolol); (methyl-4-[2-hydroxy-3-[(1-methylethyl)aminopropoxy]]-benzenepropanoate HC1) (esmolol): (erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol): (1-(tert.butylamino)-3-[O-(2-propynyloxy)phenoxy]-2-propanol (pargolol): (1-(tert.butylamino)-3-[o-(6-hydrazinv-3-pyridazinyl)-phenoxy]-2-propanol diHCl) (prizidilol); ((-)-2-hydroxy-5-[(R)-1-hydroxy-2-[(R)-(1-methyl-3-phenylpropyl)amino]ethyl]benzamide); (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)-propoxy]-7-methyl-5H-furo[3,2-g][1]-benzopyran-5-one) (iprocrolol): ((-)-5-(tert.butylamino)-2-hydroxypropoxy]-3,4-dihydro-1-(2H)-naphthalenone HC1) (levobunolol): (4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benziso- thiazole HC1); (4-[3-(tert.butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril HC1): ((±)-N-2-[4-(2-hydroxy-3-isopropyl aminopropoxy)-phenyl]ethyl-N'-isopropylurea) (pafenolol); (3-[[(2-trifluoroacetamido)ethyl]amino]-1-phenoxy- propan-2-ol): (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro-2.3-dihydro-3-oxo-5-pyridazinyl)ethylenediamine): ((±)-N-[3-acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]-propoxy]phenyl]butanamide) (acebutolol); ((±)-4'-[3-(tert-butylamino)-2-hydroxypropoxy]spiro-[cyclohexane-1,2'-indan]-1'-one) (spirendolol); (7-[3-[[2-hydroxy-3-[(2-methylindol-4-yl)oxy]propyl]-amino]butyl]thiophylline) (teoprolol): ((±)-1-tert.butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tertatolol); ((±)-1-tert.butylamino-3-(2,3-xylyloxy)-2-propanol HC1) (xibenolol): (8-[3-(tert.butylamino)-2-hydroxypropoxy]-5-methyl- coumarin) (bucumolol): (2-(3-·(tert.butylamino)-2-hydroxy-propoxy)benzonitrile HC1) (bunitrolol): ((±)-2'-[3-(tert-butylamino)-2-hydroxypropoxy-5'-fluorobutyrophenone) (butofilolol): (]1-(carbazol-4-yloxy)-3-(isopropylamino)-2-propanol) (carazolol); (5-(3-tert.butylamino-2-hydroxy)peopoxy-3,4-dihydro- carbostyril HC1) (carteolol): (1-(tert.butylamino)-3-(2.5-dichlorophenoxy)-2-propanol) (cloranolol); (1-(inden-4(or 7)-yloxy)-3-(isopropylamino)-2-propanol HC1) (indenolol); (1-isopropylamino-3-[(2-methylindol-4-yl)oxy]-2-propanol) (mepindolol): (1-(4-acetoxy-2.3.5-trimethylphenoxy)-3-isopropylaminopropan-2-ol) (metipranolol); (1-(isopropylamino)-3-(o-methoxyphenoxy)-3-[(1-methyi- ethyl)amino]-2-propanol) (moprolol); ((1-tert.butylamino)-3-[(5:6,7,8-tetrahydro-cis-6,7-dihydroxy-l-naphthyl)oxy]-2-propanol) (nadolol); ((S)-1-(2-cyclopentylphenoxy)-3-[(1,1-dimethylethyl)-amino]-2-propanol sulfate (2:1)) (penbutolol); (4'-[1-hydroxy-2-(amino)ethyl]methanesulfonanilide) (sotalol); (2-methyl-3-[4-(2-hydroxy-3-tert.butylaminopropoxy)-phenyl]-7-methoxy-isoquinolin-l-(2H)-one); (1-(4-(2-(4-fluorophenyloxy)ethoxy)phenoxy)-3-iso- propylamino-2-propanol HC1): ((-)-p-[3-[(3,4-dimethoxyphenethyl)amino]-2-hydroxy- propoxy]-B-methylcinnamonitrile) (pacrinolol); ((±)-2-(3'-tert.butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole HC1) (arotinolol); ((±)-1-[p-[2-(cyclopropylmethoxy)ethoxy]phenoxy]-3-(isopropylamino)-2-propanol) (cicloprolol); ((±)-1-[(3-chloro-2-methylindol-4-yl)oxy]-3-[(2-phenoxyethyl)amino]-2-propanol) (indopanolol); ((±)-6-[[2-[[3-(p-butoxyphenoxy)-2-hydroxypropylj- amino]ethyljaminoj-1,3-dimethyluracil) (pirepolol): (4-(cyclohexylamino)-1-(1-naphtholenyloxy)-2-butanol); (1-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropylj- aminaethylJhydantoin HC1); (3.4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-benzopyran) (nipradolol); a and B-Adreneraic Blockinar Agents: ((±)-1-tert-butylamino)-3-[o-[2-(3-methyl-5-isoxazolyl)vinyi]phenoxy]-2-propanol) (isoxaprolol): (1-isopropylamino-3-(4-(2-nitroxyethoxy)phenoxy)-2-propanol HC1): (4-hydroxy-cx-[[3-(4-methoxyphenyl)-1-methylpropyl]-aminomethyl]-3-(methylsulfinyl)-benzmethanol HC1) (sulfinalol): (5-[1-hydroxy-2-[[2-(o-methoxyphenoxy)ethyl]amino]-ethyl]-2-methylbenzenesulfonamide HC1); (5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-salicylamide HC1) (labetalol); (1-((3-chloro-2-methyl-1H-indol-4-yl)oxy)-3-((2-phenoxyethyl)amino)-2-propanol-hydrogenmalonate) (ifendolol): (4-(2-hydroxy-3-[(1-methyl-3-phenylpropyl)amino]-propoxy)benzeneacetamide): (1-[3-[[3-(1-naphthoxy)-2-hydroxypropyl]-amino]-3.3-dimethyl-propyl]-2-benzimidazolinone): (3-(1-(2-hydroxy-2-(4-chlorophenylethyl)-4-piperidyl)-3.4-dihydroxy)quinoxolin-2(1H)-one);

Claim 17

CNS-Acting Agents: clonidine; methyldopa:

Claim 18

CNS-Acting Agents: clonidine; methyldopa:

Claim 19

Adrenergic Neuron Blocking Agents: guanethidine; reserpine and other rauwolfia alkaloids such as rescinnamine;

Claim 20

Adrenergic Neuron Blocking Agents: guanethidine; reserpine and other rauwolfia alkaloids such as rescinnamine;

Claim 21

Vasodilators: diazoxide; hydralazine; minoxidil;

Claim 22

Vasodilators: diazoxide; hydralazine; minoxidil;

Claim 23

Angiotensin I Converting Enzyme Inhibitors: 1-(3-mercapto-2-methyl-l-oxopropyl)-L-proline (captopril); (1-(4-ethoxycarbonyl-2.4(R.R)-dimethylbutanoyl)-indoline-2(S)-carboxylic acid): (2-[2-[[1-(ethoxycarbonyl)-3-phenyl-propyl]amino]-1- oxopropyl]-1.2.3.4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-1-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1- oxopropyl]octahydro-1H-indole-2-carboxylic acid HC1); (N-cyclopentyl-N-(3-(2,2-dimethyl-1-oxopropyl)thiol-2-methyl-1-oxopropyl)glycine) (pivalopril); ((2R.4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid); (1-(N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis,syn-octahydroindol-2(S)-carboxylic acid HC1): ((-)-(S)-1-[(S)-3-mercapto-2-methyl-1-oxopropyl]-indoline-2-carboxylic acid); ([1(S),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-phenylthio-L-proline; (3-([1-ethoxycarbonyl-3-phenyl-(lS)-propyl]amino)-2,3,4.5-tetrahydco-2-oxo-1-(3S)-benzazepine-1- acetic acid HC1): (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the S-methyl analogue: (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril): N-[1-(S)-carboxy-3-phenylpropyl]-L-alanyl-1-proline: N 2- [1-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proline (lysinopril);

Claim 24

Angiotensin I Converting Enzyme Inhibitors: 1-(3-mercapto-2-methyl-l-oxopropyl)-L-proline (captopril); (1-(4-ethoxycarbonyl-2.4(R.R)-dimethylbutanoyl)-indoline-2(S)-carboxylic acid): (2-[2-[[1-(ethoxycarbonyl)-3-phenyl-propyl]amino]-1- oxopropyl]-1.2.3.4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-1-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1- oxopropyl]octahydro-1H-indole-2-carboxylic acid HC1); (N-cyclopentyl-N-(3-(2,2-dimethyl-1-oxopropyl)thiol-2-methyl-1-oxopropyl)glycine) (pivalopril); ((2R.4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid); (1-(N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis,syn-octahydroindol-2(S)-carboxylic acid HC1): ((-)-(S)-1-[(S)-3-mercapto-2-methyl-1-oxopropyl]-indoline-2-carboxylic acid); ([1(S),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-phenylthio-L-proline; (3-([1-ethoxycarbonyl-3-phenyl-(lS)-propyl]amino)-2,3,4.5-tetrahydco-2-oxo-1-(3S)-benzazepine-1- acetic acid HC1): (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the S-methyl analogue: (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril): N-[1-(S)-carboxy-3-phenylpropyl]-L-alanyl-1-proline: N 2- [1-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proline (lysinopril);

Claim 25

Other Antihypertensive Agents: aminophylline: cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; trimethaphan camsylate;

Claim 26

Other Antihypertensive Agents: aminophylline: cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; trimethaphan camsylate;

Claim 27

including pharmaceutical salt and ester forms thereof.

Claim 28

including pharmaceutical salt and ester forms thereof.